Pretreatment with ethinylestradiol-drospirenone and metformin enhances ovulation and pregnancy in women with polycystic ovary syndrome
DOI:
https://doi.org/10.18203/2320-1770.ijrcog20243578Keywords:
Ethinylestradiol-drospirenone, PCOS, Ovulation induction, MetforminAbstract
Background: Polycystic ovary syndrome (PCOS) is a major cause of anovulatory infertility and affects 5-10% women of reproductive age. High serum anti-mullerian hormone (AMH) is associated with lack of ovulation in PCOS women. Combined oral contraceptives containing ethinylestradiol and drospirenone suppress androgen production and reduce AMH concentration which may optimize the women with PCOS for better response to ovulation induction. This study aimed to assess the effects of ethinylestradiol-drospirenone (EE-DRSP) and metformin combination as pretreatment for ovulation induction in polycystic ovary syndrome in comparison to metformin only pretreatment.
Methods: This was a randomized controlled trial conducted on a total 62 subfertile PCOS women having high serum AMH (≥5 ng/dl). They were randomly assigned into 2 groups. In group A 31 participants received EE-DRSP and metformin combination and in group B 31 participants received only metformin for 3 months. After 3 months the participants had ovulation induction with letrozole for 3 cycles. The outcome variables were the rates of ovulation and pregnancy.
Results: Ovulation rate per cycle was higher in group A than group B. Cumulative ovulation rate per participant was also 1.36 times higher in group A than B (100.0% versus 73.3%). Cumulative pregnancy rate was 1.91 times higher in combination group than metformin alone group (67.7% versus 35.5%).
Conclusions: Pretreatment with ethinylestradiol-drospirenone and metformin for three months before ovulation induction is more effective than metformin only in terms of higher ovulation and pregnancy rate in subfertile PCOS women.
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References
Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370:1828-31.
Franks S. Polycystic ovary syndrome in adolescents. Int J Obes. 2008;32(7):1035-41.
Orio F, Palomba S. Endocrinology: new guidelines for the diagnosis and treatment of PCOS. Nat Rev Endocrinol. 2014;10:130-2.
Williams T, Mortada R, Porter S. Diagnosis and treatment of polycystic ovary syndrome. Am Fam Phys. 2016;94(2):106-13.
Hajishafiha M, Dehghan M, Kiarang N, Sadegh-Asadi N, Shayegh SN, Ghasemi-Rad M. Combined letrozole and clomiphene versus letrozole and clomiphene alone in infertile patients with polycystic ovary syndrome. Drug Des Devel Ther. 2013:1427-31.
Palomba S, Orio F, Zullo F. Ovulation induction in women with polycystic ovary syndrome. Fertil Steril. 2006;86:S26-7.
Panidis D, Georgopoulos NA, Piouka A, Katsikis I, Saltamavros AD, et al. The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia. Gynecol Endocrinol. 2011;27(8):587-92.
Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, et al. The physiology and clinical utility of anti-Müllerian hormone in women. Hum Reprod Update. 2014;20(3):370-85.
Mumford SL, Legro RS, Diamond MP, Coutifaris C, Steiner AZ. Baseline AMH level associated with ovulation following ovulation induction in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2016;101(9):3288-96.
Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, et al. Anti‐Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004;10(2):77-83.
Knight PG, Glister C. TGF-β superfamily members and ovarian follicle development. Reproduction. 2006;132(2):191-206.
La Marca A, Broekmans FJ, Volpe A, Fauser BC, Macklon NS. Anti-Müllerian hormone (AMH): what do we still need to know? Hum Reprod. 2009;24(9):2264-75.
Villarroel C, Merino PM, Lopez P, Eyzaguirre FC, Van Velzen A, Iniguez G, et al. Polycystic ovarian morphology in adolescents with regular menstrual cycles is associated with elevated anti-Müllerian hormone. Hum Reprod. 2011;26(10):2861-8.
Jacob SL, Field HP, Calder N, Picton HM, Balen AH, Barth JH. Anti‐Müllerian hormone reflects the severity of polycystic ovary syndrome. Clin Endocrinol. 2017;86(3):395-400.
Casadei L, Madrigale A, Puca F, Manicuti C, Emidi E, Piccione E, et al. The role of serum anti-Müllerian hormone (AMH) in the hormonal diagnosis of polycystic ovary syndrome. Gynecol Endocrinol. 2013;29(6):545-50.
Dumont A, Robin G, Catteau-Jonard S, Dewailly D. Role of anti-Müllerian hormone in pathophysiology, diagnosis and treatment of polycystic ovary syndrome: a review. Reprod Biol Endocrinol. 2015;13:1-10.
Banu J, Ishrat S, Deeba F, Anowary S, Alamgir CF, Darmini M. Impact of cyproterone acetate and ethinylestradiol on clomiphene resistant PCOS patient with high serum AMH level. J Shaheed Suhrawardy Med Coll. 2020;12(1):38-44.
Murphy AA, Cropp CS, Smith BS, Burkman RT, Zacur HA. Effect of low-dose oral contraceptive on gonadotropins, androgens, and sex hormone binding globulin in nonhirsute women. Ferti Steril. 1990;53(1):35-9.
Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception. 2000;62(1):29-38.
Kallio S, Puurunen J, Ruokonen A, Vaskivuo T, Piltonen T, Tapanainen JS. Anti-Müllerian hormone levels decrease in women using combined contraception independently of administration route. Fertil Steril. 2013;99(5):1305-10.
Van den Berg MH, Van Dulmen-den Broeder E, Overbeek A, Twisk JW, Schats R, Van Leeuwen FE, et al. Comparison of ovarian function markers in users of hormonal contraceptives during the hormone-free interval and subsequent natural early follicular phases. Hum Reprod. 2010;25(6):1520-7.
Branigan EF, Estes MA. A randomized clinical trial of treatment of clomiphene citrate-resistant anovulation with the use of oral contraceptive pill suppression and repeat clomiphene citrate treatment. Am J Obstet Gynecol. 2003;188(6):1424-30.
Salama M, Hamza H. Drospirenone containing combined oral contraceptive premedication before letrozole ovulation induction in clomiphene resistant PCOS, is it worth the wait. Gynecol Reprod Health. 2019;3(2):1-6.
Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018;33(9):1602-18.
Mes-Krowinkel MG, Louwers YV, Mulders AG, de Jong FH, Fauser BC, Laven JS. Influence of oral contraceptives on anthropomorphometric, endocrine, and metabolic profiles of anovulatory polycystic ovary syndrome patients. Fertil Steril. 2014;101(6):1757-65.
Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Eng J Med. 2014;371(2):119-29.
Palomba S, Falbo A, Giallauria F, Russo T, Tolino A, Zullo F, et al. Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome. D Care. 2010;33(2):246-51.
Palomba S, Falbo A, Zullo F, Orio Jr F. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30(1):1-50.
Chowdhury P, Banu J, Deeba F, Debnath RC, Rani C, Sultana S, et al. Pre-treatment with cyproterone acetate plus ethinylestradiol enhances ovarian response in women with polycystic ovary syndrome. Int J Reprod Contracept Obstet Gynecol. 2023;12(10):2320-70.
Azargoon A, Toussy JA, Darbanan FF. Pregnancies following the use of sequential treatment of metformin and incremental doses of letrozole in clomiphenresistant women with polycystic ovary syndrome. Iran J Reprod Med. 2012;10(1):33.
Dursun F, Güven A, Yursun F, Güven A, Yıldız M. Assessment of anti-Müllerian hormone level in the management of adolescents with polycystic ovary syndrome. J Clin Res Pediatr Endocrinol. 2016;8(1):55.
Medeiros LR, Colonetti T, Nagib EC, Uggioni ML, Junior JC, Ceretta L, et al. Anti-Müllerian hormone levels after metformin treatment in polycystic ovary syndrome: a systematic review and meta-analysis. Obes Res Clin Pract. 2023;17(4):288-97.
Mohsin RA, Saeed AS, Baig MM, Khan M. Role of letrozole and metformin versus letrozole alone in ovulation induction in patients of polycystic ovarian syndrome. Pak J Med Health Sci. 2019;13(1):350-2.